PSEN2

Gene Summary

Gene:PSEN2; presenilin 2
Aliases: AD4, PS2, AD3L, STM2, CMD1V
Location:1q42.13
Summary:Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor such that, they either directly regulate gamma-secretase activity, or themselves act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:presenilin-2
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (69)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Messenger RNA
  • Signal Transduction
  • RTPCR
  • Electrophoretic Mobility Shift Assay
  • Membrane Proteins
  • Promoter Regions
  • Early Growth Response Protein 1
  • LDB2
  • Tissue Distribution
  • Stat3 protein, mouse
  • Estrogen Receptor alpha
  • MicroRNAs
  • Transcription
  • Receptors, Progesterone
  • Transcription Factor AP-1
  • Cell Cycle
  • Presenilin-2
  • TNF
  • Estrogens
  • Tetradecanoylphorbol Acetate
  • Transcription Factors
  • Cyclin D1
  • Ubiquitin-Protein Ligases
  • Up-Regulation
  • Protein Structure, Tertiary
  • Transcriptional Activation
  • Tumor Markers
  • Cancer Gene Expression Regulation
  • Breast Cancer
  • DNA-Binding Proteins
  • Immunoprecipitation
  • Response Elements
  • Receptor, erbB-2
  • Base Sequence
  • ACTN4
  • PSEN2
  • Cathepsin D
  • Chromosome 1
  • Cell Proliferation
  • Luciferases
  • Ubiquitination
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PSEN2 (cancer-related)

Kumar R, Verma V, Sharma V, et al.
A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors.
Toxicol Appl Pharmacol. 2015; 283(3):187-97 [PubMed] Related Publications
Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P<0.01) and increased expression of ER-β target TNF-α (P<0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization.

Fan P, Agboke FA, Cunliffe HE, et al.
A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer.
Eur J Cancer. 2014; 50(16):2866-76 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: Oestrogen (E2)-stimulated growth re-emerges after a c-Src inhibitor blocking E2-induced apoptosis. A resulting cell line, MCF-7:PF, is selected with features of functional oestrogen receptor (ER) and over-expression of insulin-like growth factor-1 receptor beta (IGF-1Rβ). We addressed the question of whether the selective ER modulator (SERM), 4-hydroxytamoxifen (4-OHT) or other SERMs could target ER to prevent E2-stimulated growth in MCF-7:PF cells.
METHODS: Protein levels of receptors and signalling pathways were examined by immunoblotting. Expression of mRNA was measured through real-time RT-PCR. Recruitment of ER or nuclear receptor coactivator 3 (SRC3) to the promoter of ER-target gene was detected by chromatin-immunoprecipitation (ChIP).
RESULTS: 4-OHT and other SERMs stimulated cell growth in an ER-dependent manner. However, unlike E2, 4-OHT suppressed classical ER-target genes as does the pure antioestrogen ICI 182,780 (ICI). ChIP assay indicated that 4-OHT did not recruit ER or SRC3 to the promoter of ER-target gene, pS2. Paradoxically, 4-OHT reduced total IGF-1Rβ but increased phosphorylation of IGF-1Rβ. Mechanistic studies revealed that 4-OHT functioned as an agonist to enhance the non-genomic activity of ER and activate focal adhesion molecules to further increase phosphorylation of IGF-1Rβ. Disruption of membrane-associated signalling, IGF-1R and focal adhesion kinase (FAK), completely abolished 4-OHT-stimulated cell growth.
CONCLUSIONS: This study is the first to recapitulate a cellular model in vitro of acquired tamoxifen resistance developed in athymic mice in vivo. Importantly, it provides a rationale that membrane-associated pathways may be valuable therapeutic targets for tamoxifen resistant patients in clinic.

Chottanapund S, Van Duursen MB, Navasumrit P, et al.
Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts.
Toxicol In Vitro. 2014; 28(7):1215-21 [PubMed] Related Publications
Targeting the estrogen pathway has been proven effective in the treatment for estrogen receptor positive breast cancer. There are currently two common groups of anti-estrogenic compounds used in the clinic; Selective Estrogen Receptor Modulators (SERMs, e.g. tamoxifen) and Selective Estrogen Enzyme Modulators (SEEMs e.g. letrozole). Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which make them potential candidates in hormonal treatment of breast cancer. Here we used a co-culture model in which we previously demonstrated that primary human breast adipose fibroblasts (BAFs) can convert testosterone to estradiol, which subsequently results in estrogen receptor-mediated breast cancer T47D cell proliferation. In the presence of testosterone in this model, we examined the effect of letrozole, resveratrol and melatonin on cell proliferation, estradiol (E2) production and gene expression of CYP19A1, pS2 and Ki-67. Both melatonin and resveratrol were found to be aromatase inhibitors in this co-culture system, albeit at different concentrations. Our co-culture model did not provide any indications that melatonin is also a selective estrogen receptor modulator. In the T47D-BAF co-culture, a melatonin concentration of 20 nM and resveratrol concentration of 20 μM have an aromatase inhibitory effect as potent as 20 nM letrozole, which is a clinically used anti-aromatase drug in breast cancer treatment. The SEEM mechanism of action of especially melatonin clearly offers potential advantages for breast cancer treatment.

Manjegowda CM, Deb G, Limaye AM
Epigallocatechin gallate induces the steady state mRNA levels of pS2 and PR genes in MCF-7 breast cancer cells.
Indian J Exp Biol. 2014; 52(4):312-6 [PubMed] Related Publications
Investigations using in vitro and in vivo models of breast carcinogenesis have demonstrated anti-neoplastic activity of the green tea polyphenol, epigallocatechin gallate (EGCG). Although a number of molecular targets of EGCG have been identified, its impact on the expression of estrogen target genes is not completely understood. Here, we examined the mRNA expression levels of two estrogen target genes, namely Trefoil Factor 1 (pS2) and Progesterone Receptor (PR) in MCF-7 cells treated with EGCG. We observed that treatment with 40 microM EGCG, which caused only 20% decrease in cell viability, resulted in increased steady state expression levels of pS2 and PR mRNA. This suggests that EGCG may exert its biological activities, at least in part, by influencing the expression of estrogen target genes.

Tints K, Prink M, Neuman T, Palm K
LXXLL peptide converts transportan 10 to a potent inducer of apoptosis in breast cancer cells.
Int J Mol Sci. 2014; 15(4):5680-98 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Degenerate expression of transcription coregulator proteins is observed in most human cancers. Therefore, in targeted anti-cancer therapy development, intervention at the level of cancer-specific transcription is of high interest. The steroid receptor coactivator-1 (SRC-1) is highly expressed in breast, endometrial, and prostate cancer. It is present in various transcription complexes, including those containing nuclear hormone receptors. We examined the effects of a peptide that contains the LXXLL-motif of the human SRC-1 nuclear receptor box 1 linked to the cell-penetrating transportan 10 (TP10), hereafter referred to as TP10-SRC1LXXLL, on proliferation and estrogen-mediated transcription of breast cancer cells in vitro. Our data show that TP10-SRC1LXXLL induced dose-dependent cell death of breast cancer cells, and that this effect was not affected by estrogen receptor (ER) status. Surprisingly TP10-SRC1LXXLL severely reduced the viability and proliferation of hormone-unresponsive breast cancer MDA-MB-231 cells. In addition, the regulation of the endogenous ERα direct target gene pS2 was not affected by TP10-SRC1LXXLL in estrogen-stimulated MCF-7 cells. Dermal fibroblasts were similarly affected by treatment with higher concentrations of TP10-SRC1LXXLL and this effect was significantly delayed. These results suggest that the TP10-SRC1LXXLL peptide may be an effective drug candidate in the treatment of cancers with minimal therapeutic options, for example ER-negative tumors.

Almenar-Queralt A, Falzone TL, Shen Z, et al.
UV irradiation accelerates amyloid precursor protein (APP) processing and disrupts APP axonal transport.
J Neurosci. 2014; 34(9):3320-39 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Overexpression and/or abnormal cleavage of amyloid precursor protein (APP) are linked to Alzheimer's disease (AD) development and progression. However, the molecular mechanisms regulating cellular levels of APP or its processing, and the physiological and pathological consequences of altered processing are not well understood. Here, using mouse and human cells, we found that neuronal damage induced by UV irradiation leads to specific APP, APLP1, and APLP2 decline by accelerating their secretase-dependent processing. Pharmacological inhibition of endosomal/lysosomal activity partially protects UV-induced APP processing implying contribution of the endosomal and/or lysosomal compartments in this process. We found that a biological consequence of UV-induced γ-secretase processing of APP is impairment of APP axonal transport. To probe the functional consequences of impaired APP axonal transport, we isolated and analyzed presumptive APP-containing axonal transport vesicles from mouse cortical synaptosomes using electron microscopy, biochemical, and mass spectrometry analyses. We identified a population of morphologically heterogeneous organelles that contains APP, the secretase machinery, molecular motors, and previously proposed and new residents of APP vesicles. These possible cargoes are enriched in proteins whose dysfunction could contribute to neuronal malfunction and diseases of the nervous system including AD. Together, these results suggest that damage-induced APP processing might impair APP axonal transport, which could result in failure of synaptic maintenance and neuronal dysfunction.

Gao QG, Chan HY, Man CW, Wong MS
Differential ERα-mediated rapid estrogenic actions of ginsenoside Rg1 and estren in human breast cancer MCF-7 cells.
J Steroid Biochem Mol Biol. 2014; 141:104-12 [PubMed] Related Publications
Recent studies indicated that both estren and Rg1 appear to be able to activate mitogen-activated protein kinase (MAPK) pathway in estrogen responsive cells. Rg1 could lead to MAPK activation through ligand-independent activation of estrogen receptor (ER), while estren could activate the Src-MAPK pathway in an ERE-independent manner. Thus, it is important to understand the mechanistic insights on the difference in transcriptional activation between estren and Rg1. The present study also addressed the differential abilities of Rg1 and estren in terms of the ability to activate ER and the ability to induce ER translocation in MCF-7 cells. Our data indicated that Rg1 could increase pS2 gene expression, and could recruit the co-activator steroid receptor co-activator-1 (SRC-1) to the pS2 promoter. Rg1 could also induce ERα nuclear translocation as well as ERα phosphorylation at Ser118 principally in the cytoplasm in MCF-7 cells. We deduced that estren induced ERE-dependent transcriptional activity and activated ERα at Ser118 occurred in the nucleus of MCF-7 cells. However, it was found to decrease pS2 gene expression and failed to induce the recruitment of SRC-1 to the pS2 promoter in MCF-7 cells. Our results suggest that the abilities of Rg1 and estren to regulate pS2 gene expression, to recruit co-activators as well as to induce sub-cellular distribution of ERα are dramatically different.

Hahm ER, Singh SV
Diallyl trisulfide inhibits estrogen receptor-α activity in human breast cancer cells.
Breast Cancer Res Treat. 2014; 144(1):47-57 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Organosulfur compounds from garlic effectively inhibit growth of transplanted as well as spontaneous cancers in preclinical animal models without any adverse side effects. However, the mechanisms underlying anticancer effect of this class of compounds are not fully understood. This study reports, for the first time, that garlic organosulfide diallyl trisulfide (DATS) inhibits estrogen receptor-α (ER-α) activity in human breast cancer cells. Exposure of MCF-7 and T47D cells to DATS resulted in downregulation of ER-α protein, which peaked between 12- and 24-h post-treatment. DATS was relatively more effective in suppressing ER-α protein expression compared with its mono and disulfide analogs. The 17β-estradiol (E2)-induced expression of pS2 and cyclin D1, ER-α target gene products, was also decreased in the presence of DATS. Downregulation of ER-α protein expression resulting from DATS treatment was accompanied by a decrease in nuclear levels of ER-α protein, ER-α mRNA suppression, and inhibition of ERE2e1b-luciferase reporter activity. DATS-mediated inhibition of cell viability and apoptosis induction were not affected in the presence of E2. In agreement with these results, ectopic expression of ER-α in MDA-MB-231 cell line failed to confer any protection against cell proliferation inhibition or apoptosis induction resulting from DATS exposure. DATS treatment caused a decrease in protein levels of peptidyl-prolyl cis-trans isomerase (Pin1), and overexpression of Pin1 partially attenuated ER-α downregulation by DATS. DATS-induced apoptosis was modestly but significantly augmented by overexpression of Pin1. In conclusion, this study identifies ER-α as a novel target of DATS in mammary cancer cells.

Won YS, Lee JH, Kwon SJ, et al.
α-Mangostin-induced apoptosis is mediated by estrogen receptor α in human breast cancer cells.
Food Chem Toxicol. 2014; 66:158-65 [PubMed] Related Publications
In this study, we evaluated the effects of α-mangostin on cell growth inhibition and induction of apoptosis in MCF-7 ERα-positive human breast cancer cells. Our results showed that α-mangostin inhibited MCF-7 cell proliferation whereas ERα-negative MDA-MB-231 cells were less sensitive to the agent. Additionally, α-mangostin effectively induced apoptosis as evidenced by the appearance of apoptotic nuclei observed with Hoechst 33258 staining and evaluation of sub-G1 DNA contents by flow cytometry. α-Mangostin also activated caspases-8, -9, and -7; increased the protein levels of Bax, p53, and cytosolic cytochrome c; and induced PARP cleavage while reducing Bid and Bcl-2 protein expression. In addition, apoptosis-inducing factor (AIF) was transported from mitochondria to the cytosol after α-mangostin treatment. α-mangostin also induced apoptosis in 17-β-estradiol (E2)-stimulated MCF-7 cells in parallel with the non-stimulated cells. Moreover, treatment with 10μM α-mangostin for 48h specifically decreased the expression of ERα and pS2, an estrogen-responsive gene, in MCF-7 cells. Furthermore, knockdown of ERα expression in MCF-7 cells with siRNA attenuated α-mangostin-induced cell growth inhibition and caspase-7 activation. These results suggest that ERα is required for α-mangostin-induced growth inhibition and apoptosis in human breast cancer cells. Therefore, α-mangostin may be used to prevent and treat of ER-positive breast cancer.

Collins DC, Cocchiglia S, Tibbitts P, et al.
Growth factor receptor/steroid receptor cross talk in trastuzumab-treated breast cancer.
Oncogene. 2015; 34(4):525-30 [PubMed] Related Publications
Treatment with tyrosine kinase inhibitors (TKIs) including trastuzumab has revolutionized the management of HER2-positive breast cancer. Recent evaluation of clinical trial data suggests that a subset of HER2/ER double-positive cancers may not receive significant benefit from the TKI therapy. Here we investigate the cross talk between HER2 and ER in breast cancer and monitor the effect of trastuzumab on the tyrosine kinase effector transcription factor Myc. In HER2-positive breast cancer patients treated with neoadjuvant trastuzumab, steroid receptor-negative status (ER and PR negative) of pre-treatment biopsies predicted pathological complete response (pCR) (n=31 patients, P=0.0486), whereas elevated Myc protein inversely associated with pCR (P=0.0446). Liquid chromatography mass spectrometry identified the corepressor SMRT as a novel Myc-interacting protein. Trastuzumab treatment enhanced Myc-SMRT interactions in HER2-overexpressing breast cancer cells (LCC1) and inhibited expression of the Myc target gene survivin. In HER2-low, ER-positive steroid-dominant cells (MCF7), trastuzumab therapy repressed Myc-SMRT interactions and upregulated survivin expression. Trastuzumab treatment induced ER-CBP interactions, enhanced ER transcriptional activity and upregulated expression of the ER target gene pS2. The absence of pS2 expression in pre-treatment biopsies predicted pCR to neoadjuvant trastuzumab in breast cancer patients (n=25, P=0.0089) and pS2 expression associated with residual cancer burden (P=0.0196). Furthermore, metastatic tissues from patients who had failed trastuzumab therapy were pS2 positive. In HER2-overexpressing cells, trastuzumab treatment can repress Myc transcriptional activity and clinical response is favorable. However, with co-expression of the steroid pathway, this inhibition is lost and response to treatment is often poor.

Fabian CJ, Kimler BF, Donnelly JE, et al.
Favorable modulation of benign breast tissue and serum risk biomarkers is associated with > 10 % weight loss in postmenopausal women.
Breast Cancer Res Treat. 2013; 142(1):119-32 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
We conducted a phase II feasibility study of a 6-month behavioral weight loss intervention in postmenopausal overweight and obese women at increased risk for breast cancer and the effects of weight loss on anthropomorphic, blood, and benign breast tissue biomarkers. 67 women were screened by random peri-areolar fine-needle aspiration, 27 were registered and 24 participated in the interventional phase. The 24 biomarker evaluable women had a median baseline BMI of 34.2 kg/m(2) and lost a median of 11 % of their initial weight. Significant tissue biomarker modulation after the 6-month intervention was noted for Ki-67 (if restricted to the 15 women with any Ki-67 at baseline, p = 0.041), adiponectin to leptin ratio (p = 0.003); and cyclin B1 (p = 0.001), phosphorylated retinoblastoma (p = 0.005), and ribosomal S6 (p = 0.004) proteins. Favorable modulation for serum markers was observed for sex hormone-binding globulin (p < 0.001), bioavailable estradiol (p < 0.001), bioavailable testosterone (p = 0.033), insulin (p = 0.018), adiponectin (p = 0.001), leptin (p < 0.001), the adiponectin to leptin ratio (p < 0.001), C-reactive protein (p = 0.002), and hepatocyte growth factor (p = 0.011). When subdivided by <10 or >10 % weight loss, change in percent total body and android (visceral) fat, physical activity, and the majority of the serum and tissue biomarkers were significantly modulated only for women with >10 % weight loss from baseline. Some factors such as serum PAI-1 and breast tissue pS2 (estrogen-inducible gene) mRNA were not significantly modulated overall but were when considering only those with >10 % weight loss. In conclusion, a median weight loss of 11 % over 6 months resulted in favorable modulation of a number of anthropomorphic, breast tissue and serum risk and mechanistic markers. Weight loss of 10 % or more should likely be the goal for breast cancer risk reduction studies in obese women.

Malissein E, Meunier E, Lajoie-Mazenc I, et al.
RhoA and RhoC differentially modulate estrogen receptor α recruitment, transcriptional activities, and expression in breast cancer cells (MCF-7).
J Cancer Res Clin Oncol. 2013; 139(12):2079-88 [PubMed] Related Publications
PURPOSE: RhoA and RhoC are closely related, small GTPases that are clearly involved in breast cancer tumorigenesis. Nonetheless, their specific roles in the control of estrogen receptor alpha (ERα) activities have not been elucidated.
METHODS: We used siRNA sequences to specifically down-regulate RhoA and RhoC expression in ERα-positive breast adenocarcinoma MCF-7 cells. We then analyzed the consequences of down-regulation on ERα expression, ERα recruitment to the promoters of four target genes, and the mRNA levels of those genes.
RESULTS: We demonstrated that RhoA and RhoC clearly and similarly modulated ERα recruitment to the vitellogenin estrogen responsive element (ERE) present in a luciferase reporter gene and to the promoters of progesterone receptor (PR), cathepsin D, and pS2 genes. Besides, RhoA up-regulated the ERE-luciferase reporter gene activity and PR mRNA expression and tended to down-regulate cathepsin D and pS2 mRNA expression. Conversely, RhoC inhibition had no significant effect at the mRNA level. Furthermore, RhoA inhibition, and to a lesser extent RhoC inhibition, increased ERα expression. No alteration in ERα mRNA levels was observed, suggesting potential post-translational control.
CONCLUSIONS: Taken together, our results strongly suggest that RhoA and RhoC play different, but clear, roles in ERα signaling. These GTPases are definitely involved, along with RhoB, in ERα recruitment and, to some extent, ERα cofactor balance. We hypothesize a differential role of RhoA in breast cancer tumors that depend on hormone status.

Okuhira K, Demizu Y, Hattori T, et al.
Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells.
Cancer Sci. 2013; 104(11):1492-8 [PubMed] Related Publications
Manipulation of protein stability with small molecules has a great potential for both basic research and clinical therapy. Recently, we have developed a series of hybrid small molecules named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser) that induces degradation of target proteins via ubiquitin-proteasome system. Here we report the activities of SNIPER(ER) that targets estrogen receptor alpha (ERα) for degradation. SNIPER(ER) induced degradation of ERα and inhibited estrogen-dependent expression of pS2 gene in an estrogen-dependent breast cancer cell line MCF-7. A proteasome inhibitor MG132 and siRNA-mediated downregulation of cIAP1 abrogated the SNIPER(ER)-induced ERα degradation, suggesting that the ERα is degraded by proteasome subsequent to cIAP1-mediated ubiquitylation. Intriguingly, after the ERα degradation, the SNIPER(ER)-treated MCF-7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, a marker of necrosis, from the cells. Following the ERα degradation, reactive oxygen species (ROS) was produced in the SNIPER(ER)-treated MCF-7 cells, and an anti-oxidant N-acetylcysteine inhibited the necrotic cell death. These results indicate that SNIPER(ER) induces ERα degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERα-positive breast cancers.

Fenne IS, Helland T, Flågeng MH, et al.
Downregulation of steroid receptor coactivator-2 modulates estrogen-responsive genes and stimulates proliferation of mcf-7 breast cancer cells.
PLoS One. 2013; 8(7):e70096 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The p160/Steroid Receptor Coactivators SRC-1, SRC-2/GRIP1, and SRC-3/AIB1 are important regulators of Estrogen Receptor alpha (ERα) activity. However, whereas the functions of SRC-1 and SRC-3 in breast tumourigenesis have been extensively studied, little is known about the role of SRC-2. Previously, we reported that activation of the cAMP-dependent protein kinase, PKA, facilitates ubiquitination and proteasomal degradation of SRC-2 which in turn leads to inhibition of SRC-2-coactivation of ERα and changed expression of the ERα target gene, pS2. Here we have characterized the global program of transcription in SRC-2-depleted MCF-7 breast cancer cells using short-hairpin RNA technology, and in MCF-7 cells exposed to PKA activating agents. In order to identify genes that may be regulated through PKA-induced downregulation of SRC-2, overlapping transcriptional targets in response to the respective treatments were characterized. Interestingly, we observed decreased expression of several breast cancer tumour suppressor genes (e.g., TAGLN, EGR1, BCL11b, CAV1) in response to both SRC-2 knockdown and PKA activation, whereas the expression of a number of other genes implicated in cancer progression (e.g., RET, BCAS1, TFF3, CXCR4, ADM) was increased. In line with this, knockdown of SRC-2 also stimulated proliferation of MCF-7 cells. Together, these results suggest that SRC-2 may have an antiproliferative function in breast cancer cells.

Donley C, McClelland K, McKeen HD, et al.
Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen.
Oncogene. 2014; 33(26):3441-50 [PubMed] Related Publications
FKBPL has been implicated in processes associated with cancer, including regulation of tumor growth and angiogenesis with high levels of FKBPL prognosticating for improved patient survival. Understanding how FKBPL levels are controlled within the cell is therefore critical. We have identified a novel role for RBCK1 as an FKBPL-interacting protein, which regulates FKBPL stability at the post-translational level via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-β-estradiol and interact within heat shock protein 90 chaperone complexes, together with estrogen receptor-α (ERα). Furthermore, FKBPL and RBCK1 associate with ERα at the promoter of the estrogen responsive gene, pS2, and regulate pS2 levels. MCF-7 clones stably overexpressing RBCK1 were shown to have reduced proliferation and increased levels of FKBPL and p21. Furthermore, these clones were resistant to tamoxifen therapy, suggesting that RBCK1 could be a predictive marker of response to endocrine therapy. RBCK1 knockdown using targeted small interfering RNA resulted in increased proliferation and increased sensitivity to tamoxifen treatment. Moreover, in support of our in vitro data, analysis of mRNA microarray data sets demonstrated that high levels of FKBPL and RBCK1 correlated with increased patient survival, whereas high RBCK1 predicted for a poor response to tamoxifen. Our findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy.

Wierer M, Verde G, Pisano P, et al.
PLK1 signaling in breast cancer cells cooperates with estrogen receptor-dependent gene transcription.
Cell Rep. 2013; 3(6):2021-32 [PubMed] Related Publications
Polo-like kinase 1 (PLK1) is a key regulator of cell division and is overexpressed in many types of human cancers. Compared to its well-characterized role in mitosis, little is known about PLK1 functions in interphase. Here, we report that PLK1 mediates estrogen receptor (ER)-regulated gene transcription in human breast cancer cells. PLK1 interacts with ER and is recruited to ER cis-elements on chromatin. PLK1-coactivated genes included classical ER target genes such as Ps2, Wisp2, and Serpina3 and were enriched in developmental and tumor-suppressive functions. Performing large-scale phosphoproteomics of estradiol-treated MCF7 cells in the presence or absence of the specific PLK1 inhibitor BI2536, we identified several PLK1 end targets involved in transcription, including the histone H3K4 trimethylase MLL2, the function of which on ER target genes was impaired by PLK1 inhibition. Our results propose a mechanism for the tumor-suppressive role of PLK1 in mammals as an interphase transcriptional regulator.

Pitta CA, Papageorgis P, Charalambous C, Constantinou AI
Reversal of ER-β silencing by chromatin modifying agents overrides acquired tamoxifen resistance.
Cancer Lett. 2013; 337(2):167-76 [PubMed] Related Publications
The purpose of this work is to determine the molecular mechanisms underlying tamoxifen resistance. We show here that ER-β is epigenetically silenced in a cell line with acquired tamoxifen resistance (MCF-7/TAM-R) and this could be reversed by 5-AZA-deoxycytidine (5-AZA) and trichostatin-A (TSA) pre-treatment. Subsequent treatment with 4-hydroxy-tamoxifen (4-OHT) induced ER-β nuclear translocation, upregulated pS2 and p21 levels and reduced cell viability. Transfection with an ER-β expression vector sensitized MCF-7/TAM-R cells to the growth inhibitory and pro-apoptotic effects of 4-OHT, indicating that ER-β re-expression alone is sufficient to restore sensitivity to tamoxifen. This novel finding reveals that ER-β is fundamental in overcoming acquired tamoxifen resistance and provides insights for new therapeutic protocols against breast cancer.

Tilghman SL, Townley I, Zhong Q, et al.
Proteomic signatures of acquired letrozole resistance in breast cancer: suppressed estrogen signaling and increased cell motility and invasiveness.
Mol Cell Proteomics. 2013; 12(9):2440-55 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Aromatase inhibitors, such as letrozole, have become the first-line treatment for postmenopausal women with estrogen-dependent breast cancer. However, acquired resistance remains a major clinical obstacle. Previous studies demonstrated constitutive activation of the MAPK signaling, overexpression of HER2, and down-regulation of aromatase and ERα in letrozole-resistant breast cancer cells. Given the complex signaling network involved in letrozole-refractory breast cancer and the lack of effective treatment for hormone resistance, further investigation of aromatase inhibitor resistance by a novel systems biology approach may reveal previously unconsidered molecular changes that could be utilized as therapeutic targets. This study was undertaken to characterize for the first time global proteomic alterations occurring in a letrozole-resistant cell line. A quantitative proteomic analysis of the whole cell lysates of LTLT-Ca (resistant) versus AC-1 cells (sensitive) was performed to identify significant protein expression changes. A total of 1743 proteins were identified and quantified, of which 411 were significantly up-regulated and 452 significantly down-regulated (p < 0.05, fold change > 1.20). Bioinformatics analysis revealed that acquired letrozole resistance is associated with a hormone-independent, more aggressive phenotype. LTLT-Ca cells exhibited 84% and 138% increase in migration and invasion compared with the control cells. The ROCK inhibitor partially abrogated the enhanced migration and invasion of the letrozole-resistant cells. Flow cytometric analyses also demonstrated an increase in vimentin and twist expression in letrozole-resistance cells, suggesting an onset of epithelial to mesenchymal transition (EMT). Moreover, targeted gene expression arrays confirmed a 28-fold and sixfold up-regulation of EGFR and HER2, respectively, whereas ERα and pS2 were dramatically reduced by 28-fold and 1100-fold, respectively. Taken together, our study revealed global proteomic signatures of a letrozole-resistant cell line associated with hormone independence, enhanced cell motility, EMT and the potential values of several altered proteins as novel prognostic markers or therapeutic targets for letrozole resistant breast cancer.

Lin SX, Poirier D, Adamski J
A challenge for medicinal chemistry by the 17β-hydroxysteroid dehydrogenase superfamily: an integrated biological function and inhibition study.
Curr Top Med Chem. 2013; 13(10):1164-71 [PubMed] Related Publications
Members of the 17β-hydroxysteroid dehydrogenase (17β-HSD) superfamily perform distinct multiple catalyses by the same enzyme, apparently contradictory to the long-held beliefs regarding the high specificity of enzymes. Surprisingly, these multi-catalyses can combine synergistically in vitro and in vivo and their dysfunction may result in the stimulation of breast or prostate cancer. 17β-HSD1 possesses high estrogen activation activity, while its androgen inactivation is significant for decreasing the week concentration of dihydrotestosterone (DHT) in breast cancer cells, an important factor for cell proliferation. 17β-HSD5 can also carry out multiple catalyses in hormone-dependent cancer cells. In addition to 17β-HSDs 1 and 5 some other family members possess such dual-activity as well, and their inhibition decreases hormone- dependent cancer proliferation. The multi-specificity of 17β-HSD1 is structurally based on the pseudo-symmetric androgens that can accommodate the narrow enzyme substrate tunnel by both normal and alternative binding. The atypical family member 17β-HSD5 possesses a spacious binding site, which is accessible to several substrates. Expression of 17β- HSD1 can also control other estrogen-responsive elements such as pS2, and can regulate steroid-hormone receptors. The fundamental involvement of 17β-HSD1 in catalysis and gene regulation underlies its close relationship to breast cancer, attributable to its long evolutionary process. These observations stimulated detailed study of steroid-converting enzyme inhibition. The most significant efforts in designing 17β-HSD1 inhibitors in decades have progressed through structure activity relationship studies supported by the availability of both small and protein molecule structures, with the elimination of residual estrogenic activity in the inhibitors. The first non-estrogenic inhibitors of 17β-HSD1 to show activity in vivo (breast cancer animal model) are now reported.

Kerdivel G, Le Guevel R, Habauzit D, et al.
Estrogenic potency of benzophenone UV filters in breast cancer cells: proliferative and transcriptional activity substantiated by docking analysis.
PLoS One. 2013; 8(4):e60567 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The results from recent studies show that some benzophenones (BPs) and their hydroxylated metabolites can function as weak estrogens (E2) in the environment. However, little is known about the structure-activity relationship of these molecules. We have examined the effects of exposure to ten different BPs on the proliferation of estrogen receptor (ER)-positive breast cancer cells and on the transcriptional activity of E2-target genes. We analyzed two genes that are tightly linked with estrogen-mediated proliferation, the CXCL12 and amphiregulin genes and two classical estrogen-responsive genes, the pS2 and progesterone receptor. Significant differences in the BPs efficiency to induce cell proliferation and endogenous E2-target gene expressions were observed. Using ERE-, Sp1-, AP1- and C3-reporter genes that contain different ER-binding sites in their promoter, we also showed significant differences in the BPs efficiency in activation of the ER transactivation. Together, our analyzes showed that the most active molecule is 4-hydroxy-BP. Docking analysis of the interaction of BPs in the ligand-binding pocket of ERα suggests that the minimum structural requirement for the estrogenic activity of BPs is a hydroxyl (OH) group in the phenyl A-ring that allows interaction with Glu-353, Arg-394 or Phe-404, which enhances the stability between BPs and ERα. Our modeling also indicates a loss of interaction between the OH groups of the phenyl B-ring and His-524. In addition, the presence of some OH groups in the phenyl B-ring can create repulsion forces, which may constrain helix 12 in an unfavorable position, explaining the differential estrogenic effects of BPs. These results, together with our analysis of BPs for their potency in activation of cell proliferation and ER-mediated transcription, report an improved understanding of the mechanism and structure-activity relationship of BPs.

Faigenbaum R, Haklai R, Ben-Baruch G, Kloog Y
Growth of poorly differentiated endometrial carcinoma is inhibited by combined action of medroxyprogesterone acetate and the Ras inhibitor Salirasib.
Oncotarget. 2013; 4(2):316-28 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Type 2 endometrial carcinoma (EC) is a poorly differentiated EC. Unlike type 1 EC, which responds to hormonal treatment (progestins), type 2 EC is refractory to hormonal treatment because of its low expression of active estrogen and progesterone receptors (ER, PR). The aim of this study was to develop a novel drug combination designed to treat these aggressive type 2 EC tumors without surgery and with fertility potential preserved. We examined the effects of combined treatment with the progestin medroxyprogesterone acetate (MPA) and the Ras inhibitor S-farnesylthiosalicylic acid (FTS; Salirasib). Because FTS can induce cell differentiation in tumor cells, we examined whether FTS could induce re-differentiation of type 2 EC cells, thereby sensitizing them to MPA. We found that FTS reduced Ras-GTP, phospho- Akt, and phospho-ERK, and that these reductions all correlated with a decrease in ERα phosphorylation. Combined treatment with FTS and MPA induced stronger reduction in USPC1 type 2 EC cell numbers than the reduction induced by either drug alone. MPA caused ERα degradation. Death of the cells was caused by MPA but not by FTS. The phosphorylated ERα induces gene transcription manifested by enhanced cell proliferation and survival. The combination of FTS and MPA, by reducing the mRNA expression of ERα-mediated genes (i.e. PR, c-fos and ps2/TFF1), inhibited tumor growth and enhanced the death of type 2 EC cells. These promising results might herald a novel treatment for the highly aggressive, incurable type 2 endometrial carcinoma.

Sun X, Qin S, Fan C, et al.
Let-7: a regulator of the ERα signaling pathway in human breast tumors and breast cancer stem cells.
Oncol Rep. 2013; 29(5):2079-87 [PubMed] Related Publications
The oncogenic role of estrogen receptor (ER)α and its correlation with let-7 microRNAs (miRNAs) have been studied and confirmed in breast tumors; however, this correlation has not been investigated in breast cancer stem cells (BCSCs). In the present study, we detected the expression of let-7 and ERα in ER-positive breast tumor tissues. Furthermore, we used a FACSAria cell sorter to separate side population (SP) cells from the MCF-7 and T47-D cell lines by Hoechst 33342 staining. The expression of let-7 miRNAs, ERα and its downstream genes in SP and non-SP (NSP) cells were analyzed. In additional experiments, we transfected a plasmid expressing let-7a into SP cells isolated from the MCF-7 and T47-D cell lines in order to observe changes in the expression of downstream genes (cyclin D1 and pS2). The correlation among let-7, ERα and ERα downstream genes suggested that let-7 acts as a tumor suppressor by inhibiting ERα-mediated cellular malignant growth in ER-positive breast cancer stem cells. The suppression of ERα by the upregulation of let-7 expression may be a promising strategy for the inhibition of the ER signaling pathway and for the elimination of cancer stem cells, thus aiding in the treatment of breast cancer.

Song Y, Santen RJ, Wang JP, Yue W
Inhibitory effects of a bazedoxifene/conjugated equine estrogen combination on human breast cancer cells in vitro.
Endocrinology. 2013; 154(2):656-65 [PubMed] Related Publications
Breast cancer incidence is increased in women receiving menopausal hormone therapy with estrogen plus progestin but not with estrogen alone. The use of a tissue-selective estrogen complex (TSEC) has been proposed as a novel menopausal hormone therapy strategy to eliminate the requirement for a progestogen. Combination of bazedoxifene (BZA) with conjugated estrogens (CEs), the first TSEC, has shown beneficial effects. Whether it would exert antiestrogenic effects on breast cancer is not clear. To address this issue, we compared estradiol (E(2)) and CE alone on proliferation and apoptosis in MCF-7 breast cancer cells. CE stimulated growth of MCF-7 cells at a peak concentration 10-fold higher than required for E(2). Both CE and E(2) alone increased DNA synthesis and reduced apoptosis with activation of MAPK, Akt, and p70S6K and up-regulation of antiapoptotic factors survivin, Bcl-2, and X-linked inhibitor of apoptosis protein, These effects could be completely blocked by BZA. Gene expression studies demonstrated that CE and E(2) were equally potent on expression of cMyc, pS2, and WNT1 inducible signaling pathway protein 2, whereas the stimulatory effects of CE on progesterone receptor and amphiregulin expression were weaker than E(2). BZA effectively blocked each of these effects and showed no estrogen agonistic effects when used alone. Our results indicate that the stimulatory effects of E(2) or CE on breast cancer cells could be completely abrogated by BZA. These studies imply that the CE/BZA, TSEC, exerts antiestrogenic effects on breast cancer cells and might block the growth of occult breast neoplasms in postmenopausal women, resulting in an overall reduction in tumor incidence.

Lattrich C, Stegerer A, Häring J, et al.
Estrogen receptor β agonists affect growth and gene expression of human breast cancer cell lines.
Steroids. 2013; 78(2):195-202 [PubMed] Related Publications
Expression of estrogen receptor β (ERβ) has been described to reduce growth of cancer cell lines derived from hormone-dependent tumors, like breast cancer. In this study we tested to what extent two ERβ agonists, androgen derivative 3β-Adiol and flavonoid Liquiritigenin, would affect growth and gene expression of different ERβ-positive human breast cancer cell lines. Under standard cell culture conditions, we observed 3β-Adiol to inhibit growth of MCF-7 cells in a dose-dependent manner, whereas growth of BT-474 and MCF-10A cells was suppressed by the maximum concentration (100 nM) only. When treated in serum-free medium, all cell lines except of MDA-MB-231 were responsive to 1 nM 3β-Adiol, and ZR75-1 cells exhibited a dose-dependent antiproliferative response. Providing putative mechanisms underlying the observed growth-inhibitory effect, expression of Ki-67 or cyclins A2 and B1 was downregulated after 3β-Adiol treatment in all responsive lines. In contrast, treatment with lower doses of Liquiritigenin did not affect growth. In MCF-7 cells, the highest dose of this flavonoid exerted proliferative effects accompanied by increased expression of cyclin B1, PR and PS2, indicating unspecific activation of ERα. In conclusion, the ERβ agonists tested exerted distinct concentration-dependent and cell line-specific effects on growth and gene expression. The observed inhibitory effects of 3β-Adiol on breast cancer cell growth encourage further studies on the potential of this and other ERβ agonists as targeted drugs for breast cancer therapy.

Song Y, Santen RJ, Wang JP, Yue W
Effects of the conjugated equine estrogen/bazedoxifene tissue-selective estrogen complex (TSEC) on mammary gland and breast cancer in mice.
Endocrinology. 2012; 153(12):5706-15 [PubMed] Related Publications
A tissue-selective estrogen complex (TSEC), combining a selective estrogen receptor modulator, bazedoxifene (BZA), with conjugated equine estrogen (CEE), represents a novel strategy of menopausal hormone therapy without involving a progestin. We hypothesized that the antiestrogenic properties of BZA can also block the estrogenic effects of CEE on breast tissue and thereby prevent breast cancer in women. To test our hypothesis, the effects of estradiol (E(2)), CEE, and BZA on mammary gland and breast cancer xenografts were assessed in mouse models. In immature castrate mice, BZA completely blocked CEE- or E(2)-stimulated ductal and terminal end bud growth of mammary gland as well as estrogen-responsive gene expression. As a positive control, E(2) stimulated tumor growth in nude mice bearing MCF-7 xenografts. This effect was completely blocked by BZA as were E(2)-stimulated expression of PR, pS2 (trefoil factor 1), cMyc, and AREG; the enhancement of Ki67 and proliferating cell nuclear antigen (PCNA); and the antiapoptotic effect. CEE was much less potent than E(2) in stimulating Ki67, reducing apoptosis, and stimulating gene expression, but all effects were blocked by BZA. Unexpectedly, CEE alone, even at high doses, did not stimulate tumor growth. As confirmation of its absorption and deconjugation, CEE caused a 6-fold increase in uterine weight and stimulation of gene expression. These data support our hypothesis that the net effect of the CEE/BZA TSEC is to block estrogen action in benign and malignant breast tissue. These findings provide a rationale for a clinical study to determine whether this TSEC prevents breast cancer in women.

Min CR, Kim MJ, Park YJ, et al.
Estrogenic effects and their action mechanism of the major active components of party pill drugs.
Toxicol Lett. 2012; 214(3):339-47 [PubMed] Related Publications
Benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) are commonly used constituents of party pill drugs. They are reported to induce psychoactive effects such as euphoria and provide effects similar with other illicit drugs such as methylenedioxymethamphetamine (MDMA). A great deal of evidence has proven that party pills, as alternatives for MDMA, exert harmful effects on users. However, their toxicological effects have not been fully understood and endocrine disruptive effects are still unknown. In this study, we identified estrogenic effects of BZP and TFMPP by using in vitro and in vivo assays. BZP and TFMPP stimulated cell proliferation in a dose-dependent manner, while co-treatment with tamoxifen and BZP or TFMPP showed a decrease of E(2)-induced cell proliferation. In an estrogen sensitive reporter gene assay, BZP and TFMPP significantly increased transcriptional activities of party pill drugs. In addition, ER-related genes, PR and pS2, were significantly stimulated by BZP and TFMPP. These results indicated that BZP and TFMPP could have estrogenic activities related to the ER-mediated pathway. Unlike the in vitro assay results, BZP and TFMPP did not show significant effects on weight increase in a rodent uterotrophic assay. However, further studies would be necessary to verify the estrogenic activities of BZP and TFMPP by a chronic exposure animal study.

Maraver A, Fernandez-Marcos PJ, Herranz D, et al.
Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK.
Cancer Cell. 2012; 22(2):222-34 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Here, we have investigated the role of the Notch pathway in the generation and maintenance of Kras(G12V)-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and RBPJ are essential for the formation of NSCLCs. Of importance, pharmacologic treatment of mice carrying autochthonous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth. Treated carcinomas present reduced HES1 levels and reduced phosphorylated ERK without changes in phosphorylated MEK. Mechanistically, we show that HES1 directly binds to and represses the promoter of DUSP1, encoding a dual phosphatase that is active against phospho-ERK. Accordingly, GSI treatment upregulates DUSP1 and decreases phospho-ERK. These data provide proof of the in vivo therapeutic potential of GSIs in primary NSCLCs.

He XY, Yang WM, Tang WT, et al.
TRAV gene expression in PBMCs and TILs in patients with breast cancer analyzed by a DNA melting curve (FQ-PCR) technique for TCR α chain CDR3 spectratyping.
Neoplasma. 2012; 59(6):693-9 [PubMed] Related Publications
PURPOSE: To explore the expression of the TRAV gene in peripheral blood mononuclear cells (PBMCs) and in tumor-infiltrating lymphocytes (TILs) in the patients with breast cancer using a DNA melting curve (FQ-PCR) technique for T cell receptor (TCR) alpha chain CDR3 spectratyping. Peripheral blood samples and tissue samples were obtained from thirty breast cancer patients. Total RNA was extracted from PBMCs and tumor tissues and then reverse transcribed into cDNA. FQ-PCR was used to amplify the human TCR alpha chain CDR3 region with the primers to the TRAV and TRAC genes. TCR alpha chain CDR3 spectratyping and partial CDR3 sequencing were used to determine use of TRAV gene product in T cell responses. TCR alpha CDR3 spectratyping showed preferential usage of certain TRAV genes in the PBMCs and TILs of all patients with breast cancer. The frequencies of TRAV1.1, TRAV9, and TRAV29 exceeded 30% in PBMCs and the frequencies of TRAV1.1 and TRAV22 exceeded 30% in TILs. More than three quarters of the patients (23/30) overexpressed the same gene in both PBMCs and TILs; for example, patient-1 highly expressed TRAV9 in the PBMCs and TILs. Patients with positive or negative tumor markers of estrogen receptor (ER), progesterone receptor (PR), pS2, C-erbB-2, nm23, P53, and Ki-67 showed no significant common TRAV gene expression, but some TRAV gene preferential usage frequencies exceeded 20%. For example, five of seven patients positive for ER had high levels of expression of TRAV1.1 and TRAV3. Finally, the amino acid sequence of TCR CDR3 region showed some common motifs in some of the patients.
CONCLUSIONS: TRAV gene expression was complex and diverse in the patients with breast cancer. The TRAV gene usage may be closely related to the diversity of breast tumor antigens and the differential immune responses observed in individual patients. Research into the immunological mechanism of T cells may provide guidance for individual T cell-directed therapy for breast cancer.

Stone A, Valdés-Mora F, Gee JM, et al.
Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer.
PLoS One. 2012; 7(7):e40466 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
In the present study, we have taken the novel approach of using an in vitro model representative of tamoxifen-withdrawal subsequent to clinical relapse to achieve a greater understanding of the mechanisms that serve to maintain the resistant-cell phenotype, independent of any agonistic impact of tamoxifen, to identify potential novel therapeutic approaches for this disease state. Following tamoxifen withdrawal, tamoxifen-resistant MCF-7 cells conserved both drug resistance and an increased basal rate of proliferation in an oestrogen deprived environment, despite reduced epidermal growth-factor receptor expression and reduced sensitivity to gefitinib challenge. Although tamoxifen-withdrawn cells retained ER expression, a sub-set of ER-responsive genes, including pS2 and progesterone receptor (PgR), were down-regulated by promoter DNA methylation, as confirmed by clonal bisulphite sequencing experiments. Following promoter demethylation with 5-Azacytidine (5-Aza), the co-addition of oestradiol (E2) restored gene expression in these cells. In addition, 5-Aza/E2 co-treatment induced a significant anti-proliferative effect in the tamoxifen-withdrawn cells, in-contrast to either agent used alone. Microarray analysis was undertaken to identify genes specifically up regulated by this co-treatment. Several anti-proliferative gene candidates were identified and their promoters were confirmed as more heavily methylated in the tamoxifen resistant vs sensitive cells. One such gene candidate, growth differentiation factor 15 (GDF15), was carried forward for functional analysis. The addition of 5-Aza/E2 was sufficient to de-methylate and activate GDF15 expression in the tamoxifen resistant cell-lines, whilst in parallel, treatment with recombinant GDF15 protein decreased cell survival. These data provide evidence to support a novel concept that long-term tamoxifen exposure induces epigenetic silencing of a cohort of oestrogen-responsive genes whose function is associated with negative proliferation control. Furthermore, reactivation of such genes using epigenetic drugs could provide a potential therapeutic avenue for the management of tamoxifen-resistant breast cancer.

Liu B, Wang L, Shen LL, et al.
RNAi-mediated inhibition of presenilin 2 inhibits glioma cell growth and invasion and is involved in the regulation of Nrg1/ErbB signaling.
Neuro Oncol. 2012; 14(8):994-1006 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Gliomas are the leading cause of death among adults with primary brain malignancies. Treatment for malignant gliomas remains limited, and targeted therapies have been incompletely explored. In this study, we found that the protein expression of presenilin 2 (PS2) was significantly increased in glioma tissues, at least partially because of promoter demethylation. We further evaluated the biological functions of PS2 in U251 glioma cell proliferation, migration, invasion, and tumor growth in vivo by specific inhibition of PS2 using short hairpin RNA (shRNA). We found that PS2 depletion inhibited glioma cell growth as the result of inhibited proliferation and induced apoptosis. PS2 depletion also decreased the invasive capability of glioma cells and anchorage-independent colony formation in soft agar. Moreover, suppression of PS2 expression significantly impaired the growth of glioma xenografts in nude mice. Finally, the decrease in glioma cell growth caused by PS2 depletion seems to involve Nrg1/ErbB signaling. In summary, our data highlight the use of RNA interference (RNAi) as a tool to better understand the molecular basis of PS2 in glioma progression and to uncover new targets for the treatment of glioma.

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